Second Coordination Sphere Water Molecules and Relaxivity of Gadolinium(III) Complexes. Implications for MRI Contrast Agents

Dipolar interaction between the metal ion and proximate water molecules represents an efficient mechanism for solvent relaxation in Gd³⁺ complexes currently employed as MRI contrast agents. Besides inner sphere (metal bound) and outer sphere hydration molecules, a well-defined second coordination shell may provide an additional mechanism for paramagnetic relaxation leading to a strong enhancement of the relaxivity of the complexes. Through a careful choice of hydrogen-bond-acceptor groups on the ligand we may: (1) promote the formation of a strong interaction; (2) increase the number of water molecules in the second hydration shell; (3) decrease their average distance from the paramagnetic metal center. These possibilities have been explored by considering complexes bearing phosphinate, phosphonate and carboxoamide pendant arms, by exploiting the formation of ion-pairs with cationic substrates and inclusion compounds of these adducts with β-cyclodextrin. Finally, the contribution of this relaxation mechanism to the relaxivity of the commercially available MRI contrast agents is discussed and the NMRD data reevaluated and compared with crystallographic data.